The present invention relates to certain compounds that are useful for the inhibition of prenyl-protein transferases and the treatment of cancer. In particular, the invention relates to prenyl-protein transferase inhibitors which are efficacious in vivo as inhibitors of geranylgeranyl-protein transferase type I (GGTase-I) and that inhibit the cellular processing of both the H-Ras protein and the K4B-Ras protein.
Prenylation of proteins by prenyl-protein transferases represents a class of post-translational modification (Glomset, J. A., Gelb, M. H., and Farnsworth, C. C. (1990). Trends Biochem. Sci. 15, 139-142; Maltese, W. A. (1990). FASEB J. 4, 3319-3328). This modification typically is required for the membrane localization and function of these proteins. Prenylated proteins share characteristic C-terminal sequences including CAAX (C, Cys; A, an aliphatic amino acid; X, another amino acid), XXCC, or XCXC. Three post-translational processing steps have been described for proteins having a C-terminal CAAX sequence: addition of either a 15 carbon (farnesyl) or 20 carbon (geranylgeranyl) isoprenoid to the Cys residue, proteolytic cleavage of the last 3 amino acids, and methylation of the new C-terminal carboxylate (Cox, A. D. and Der, C. J. (1992a). Critical Rev. Oncogenesis 3:365-400; Newman, C. M. H. and Magee, A. I. (1993). Biochim. Biophys. Acta 1155:79-96). Some proteins may also have a fourth modification: palmitoylation of one or two Cys residues N-terminal to the farnesylated Cys. While some mammalian cell proteins terminating in XCXC are carboxymethylated, it is not clear whether carboxy methylation follows prenylation of proteins terminating with a XXCC motif (Clarke, S. (1992). Annu. Rev. Biochem. 61, 355-386).
For all of the prenylated proteins, addition of the isoprenoid is the first step and is required for the subsequent steps (Cox, A D. and Der, C. J. (1992a). Critical Rev. Oncogenesis 3:365-400; Cox, A. D. and Der, C. J. (1992b) Current Opinion Cell Biol. 4:1008-1016).
Three enzymes have been described that catalyze protein prenylation: farnesyl-protein transferase (FPTase), geranylgeranyl-protein transferase type I (GGPTase-I), and geranylgeranyl-protein transferase type-II (GGPTase-II, also called Rab GGPTase). These enzymes are found in both yeast and mammalian cells (Clarke, 1992;
Schafer, W. R. and Rine, J. (1992) Annu. Rev. Genet. 30:209-237). Each of these enzymes selectively uses farnesyl diphosphate or geranyl-geranyl diphosphate as the isoprenoid donor and selectively recognizes the protein substrate. FPTase farnesylates CaaX-containing proteins that end with Ser, Met, Cys, Gln or Ala. For FPTase, CaaX tetrapeptides comprise the minimum region required for interaction of the protein substrate with the enzyme. The enzymological characterization of these three enzymes has demonstrated that it is possible to selectively inhibit one with little inhibitory effect on the others (Moores, S. L., Schaber, M. D., Mosser, S. D., Rands, E., O""Hara, M. B., Garsky, V. M., Marshall, M. S., Pompliano, D. L., and Gibbs, J. B., J. Biol. Chem., 266:17438 (1991), U.S. Pat. No. 5,470,832).
The prenylation reactions have been shown genetically to be essential for the function of a variety of proteins (Clarke, 1992; Cox and Der, 1992a; Gibbs, J. B. (1991). Cell 65: 1-4; Newman and Magee, 1993; Schafer and Rine, 1992). This requirement often is demonstrated by mutating the CaaX Cys acceptors so that the proteins can no longer be prenylated. The resulting proteins are devoid of their central biological activity. These studies provide a genetic xe2x80x9cproof of principlexe2x80x9d indicating that inhibitors of prenylation can alter the physiological responses regulated by prenylated proteins.
The Ras protein is part of a signaling pathway that links cell surface growth factor receptors to nuclear signals initiating cellular proliferation. Biological and biochemical studies of Ras action indicate that Ras functions like a G-regulatory protein. In the inactive state, Ras is bound to GDP. Upon growth factor receptor activation, Ras is induced to exchange GDP for GTP and undergoes a conformational change. The GTP-bound form of Ras propagates the growth stimulatory signal until the signal is terminated by the intrinsic GTPase activity of Ras, which returns the protein to its inactive GDP bound form (D. R. Lowy and D. M. Willumsen, Ann. Rev. Biochem. 62:851-891 (1993)). Activation of Ras leads to activation of multiple intracellular signal transduction pathways, including the MAP Kinase pathway and the Rho/Rac pathway (Joneson et al., Science 271:810-812).
Mutated ras genes are found in many human cancers, including colorectal carcinoma, exocrine pancreatic carcinoma, and myeloid leukemias. The protein products of these genes are defective in their GTPase activity and constitutively transmit a growth stimulatory signal.
The Ras protein is one of several proteins that are known to undergo post-translational modification. Farnesyl-protein transferase utilizes farnesyl pyrophosphate to covalently modify the Cys thiol group of the Ras CAAX box with a farnesyl group (Reiss et al., Cell, 62:81-88 (1990); Schaber et al., J. Biol. Chem., 265:14701-14704 (1990); Schafer et al., Science, 249:1133-1139 (1990); Manne et al., Proc. Natl. Acad. Sci USA, 87:7541-7545 (1990)).
Ras must be localized to the plasma membrane for both normal and oncogenic functions. At least 3 post-translational modifications are involved with Ras membrane localization, and all 3 modifications occur at the C-terminus of Ras. The Ras C-terminus contains a sequence motif termed a xe2x80x9cCAAXxe2x80x9d or xe2x80x9cCysxe2x80x94Aaa1xe2x80x94Aaa2xe2x80x94Xaaxe2x80x9d box (Cys is cysteine, Aaa is an aliphatic amino acid, the Xaa is any amino acid) (Willumsen et al., Nature 310:583-586 (1984)). Depending on the specific sequence, this motif serves as a signal sequence for the enzymes farnesyl-protein transferase or geranylgeranyl-protein transferase, which catalyze the alkylation of the cysteine residue of the CAAX motif with a C15 or C20 isoprenoid, respectively. (S. Clarke., Ann. Rev. Biochem. 61:355-386 (1992); W. R. Schafer and J. Rine, Ann. Rev Genetics 30:209-237 (1992)). Direct inhibition of farnesyl-protein transferase would be more specific and attended by fewer side effects than would occur with the required dose of a general inhibitor of isoprene biosynthesis.
Other farnesylated proteins include the Ras-related GTP-binding proteins such as RhoB, fungal mating factors, the nuclear lamins, and the gamma subunit of transducin. James, et al., J. Biol. Chem. 269, 14182 (1994) have identified a peroxisome associated protein Pxf which is also farnesylated. James, et al., have also suggested that there are farnesylated proteins of unknown structure and function in addition to those listed above.
Inhibitors of farnesyl-protein transferase (FPTase) have been described in two general classes. The first class includes analogs of farnesyl diphosphate (FPP), while the second is related to protein :substrates (e.g., Ras) for the enzyme. The peptide derived inhibitors that have been described are generally cysteine containing molecules that are related to the CAAX motif that is the signal for protein prenylation. (Schaber et al., ibid; Reiss et. al., ibid; Reiss et al., PNAS, 88:732-736 (1991)). Such inhibitors may inhibit protein prenylation while serving as alternate substrates for the farnesyl-protein transferase enzyme, or may be purely competitive inhibitors (U.S. Pat. No. 5,141,851, University of Texas; N. E. Kohl et al., Science, 260:1934-1937 (1993); Graham, et al., J. Med. Chem., 37, 725 (1994)).
Mammalian cells express four types of Ras proteins (H-, N-, K4A-, and K4B-Ras) among which K4B-Ras is the most frequently mutated form of Ras in human cancers. The genes that encode these proteins are abbreviated H-ras, N-ras, K4A-ras and K4B-ras respectively.
H-ras is an abbreviation for Harvey-ras. K4A-ras and K4B-ras are abbreviations for the Kirsten splice variants of ras that contain the 4A and 4B exons, respectively. Inhibition of farnesyl-protein transferase has been shown to block the growth of H-ras-transformed cells in soft agar and to modify other aspects of their transformed phenotype. It has also been demonstrated that certain inhibitors of farnesyl-protein transferase selectively block the processing of the H-Ras oncoprotein intracellularly (N. E. Kohl et al., Science, 260:1934-1937 (1993) and G. L. James et al., Science, 260:1937-1942 (1993). Recently, it has been shown that an inhibitor of farnesyl-protein transferase blocks the growth of H-ras-dependent tumors in nude mice (N. E. Kohl et al., Proc. Natl. Acad. Sci U.S.A., 91:9141-9145 (1994) and induces regression of mammary and salivary carcinomas in H-ras transgenic mice (N. E. Kohl et al., Nature Medicine, 1:792-797 (1995).
Indirect inhibition of farnesyl-protein transferase in vivo has been demonstrated with lovastatin Merck and Co., Rahway, N.J.) and compactin (Hancock et al., ibid; Casey et al., ibid; Schafer et al., Science 245:379 (1989)). These drugs inhibit HMG-CoA reductase, the rate limiting enzyme for the production of polyisoprenoids including farnesyl pyrophosphate. Inhibition of farnesyl pyrophosphate biosynthesis by inhibiting HMG-CoA reductase blocks Ras membrane localization in :cultured cells.
It has been disclosed that the lysine-rich region and terminal CVIM sequence of the C-terminus of K-RasB confer resistance to inhibition of the cellular processing of that protein by certain selective FPTase inhibitors. James, et al., J. Biol. Chem. 270, 6221 (1995) Those FPTase inhibitors were effective in inhibiting the processing of H-Ras proteins. James et al. suggested that prenylation of the K4B-Ras protein by GGTase-I contributed to the resistance to the selective FPTase inhibitors.
Selective inhibitors of GGTase-I have been previously disclosed (see for example U.S. Pat. No. 5,470,832, issued November 28, 1995). Other compounds have been described as selective inhibitors of GGTase-I (see for example PCT Publication No. WO 96/21456). Combinations of a selective inhibitor of FPTase and a selective inhibitor of GGTase-I have been disclosed as useful in the treatment of cancer (PCT Publication No. WO 97/34664).
Several groups of scientists have recently disclosed compounds that are non-selective FPTase/GGTase-I inhibitors. (Nagasu et al. Cancer Research, 55:5310-5314 (1995); PCT application WO 95/25086).
It is the object of the instant invention to provide a prenyl-protein transferase inhibitor which is efficacious in vivo as an inhibitor of geranylgeranyl-protein transferase type I (GGTase-I), also known as CAAX GGTase.
It is also the object of the present invention to provide a compound which inhibits the cellular processing of both the H-Ras protein and the K4B-Ras protein.
It is also the object of the present invention to provide a compound which is efficacious in vivo as an inhibitor of the growth of cancer cells characterized by a mutated K4B-Ras protein.
A composition which comprises such an inhibitor compound is used in the present invention to treat cancer.
The present invention comprises piperazine-containing compounds which inhibit prenyl-protein transferases. Further contained in this invention are chemotherapeutic compositions containing these prenyl transferase inhibitors and methods for their production.
The compounds of this invention are illustrated by the formula A: 
The compounds of this invention are useful in the inhibition of prenyl-protein transferases and the prenylation of the oncogene protein Ras. In a first embodiment of this invention, the inhibitors of prenyl-protein transferases are illustrated by the formula A: 
wherein:
R1a and R1b are independently selected from:
a) hydrogen,
b) aryl, heterocycle, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, R10Oxe2x80x94, R11S(O)mxe2x80x94, R10C(O)NR10xe2x80x94, (R10)2NC(O)xe2x80x94, R102Nxe2x80x94C(NR10)xe2x80x94, CN, NO2, R10C(O)xe2x80x94, N3, xe2x80x94N(R10)2, or R11OC(O)NR10xe2x80x94,
c) unsubstituted or substituted C1-C6 alkyl wherein the substitutent on the substituted C1-C6 alkyl is selected from unsubstituted or substituted aryl, heterocyclic, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, R10Oxe2x80x94, R11S(O)mxe2x80x94, R10C(O)NR10xe2x80x94, (R10)2NC(O)xe2x80x94, R102Nxe2x80x94C(NR10)xe2x80x94, CN, R10OC(O)xe2x80x94, N3, xe2x80x94N(R10)2, and R11OC(O)xe2x80x94 NR10xe2x80x94;
R1c is independently selected from:
a) hydrogen,
b) unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, R10Oxe2x80x94, R11S(O)mxe2x80x94, R10C(O)NR10xe2x80x94, (R10)2NC(O)xe2x80x94, R102Nxe2x80x94C(NR10)xe2x80x94, CN, NO2, R10C(O)xe2x80x94, N3, xe2x80x94N(R10)2 or R11OC(O)NR10xe2x80x94,
c) unsubstituted or substituted C1-C6 alkyl wherein the substitutent on the substituted C1-C6 alkyl is selected from unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, R10Oxe2x80x94, R11S(O)mxe2x80x94, R10C(O)NR10xe2x80x94, (R10)2NC(O)xe2x80x94, R102Nxe2x80x94C(NR10)xe2x80x94, CN, R10C(O)xe2x80x94, N3, xe2x80x94N(R10)2 and R11OC(O)xe2x80x94NR10xe2x80x94;or two R1cs on the same carbon are combined with that carbon to form a C4-C6 cycloalkyl;
R2 and R3 are independently selected from: H; unsubstituted or substituted C1-8 alkyl, unsubstituted or substituted C2-8 alkenyl, unsubstituted or substituted C2-8 alkynyl, unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, 
xe2x80x83wherein the substituted group is substituted with one or more of: 
R2 and R3 are attached to the same C atom and are combined to form xe2x80x94(CH2)uxe2x80x94 wherein one of the carbon atoms is optionally replaced by a moiety selected from: O, S(O)m, xe2x80x94NC(O)xe2x80x94, and xe2x80x94N(COR10)xe2x80x94;
R4 is selected from H and CH3; and any two of R2, R3 and R4 are optionally attached to the same carbon atom;
R6, R7 and R7a are independently selected from: H; C1-4 alkyl, C3-6 cycloalkyl, heterocycle, aryl, aroyl, heteroaroyl, arylsulfonyl, heteroarylsulfonyl, unsubstituted or substituted with: 
R6 and R7 may be joined in a ring;
R7 and R7a may be joined in a ring;
R6a is selected from: C1-4 alkyl, C3-6 cycloalkyl, heterocycle, aryl, unsubstituted or substituted with: 
R8 is independently selected from:
a) hydrogen,
b) unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, unsubstituted or substituted C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, perfluoroalkyl, F, Cl, Br, R10Oxe2x80x94, R11S(O)mxe2x80x94, R10C(O)NR10xe2x80x94, (R10)2NC(O)xe2x80x94, R102Nxe2x80x94C(NR10)xe2x80x94, CN, NO2, R10C(O)xe2x80x94, N3, xe2x80x94N(R102, or R11OC(O)NR10xe2x80x94, and
c) C1-C6 alkyl unsubstituted or substituted by aryl, cyanophenyl, heterocycle, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, perfluoroalkyl, F, Cl, Br, R10Oxe2x80x94, R11S(O)mxe2x80x94, R10C(O)NHxe2x80x94, (R10)2NC(O)xe2x80x94, R102Nxe2x80x94C(NR10)xe2x80x94, CN, R10C(O)xe2x80x94, N3, xe2x80x94N(R102, or R10OC(O)NHxe2x80x94;
R9 is selected from:
a) hydrogen,
b) alkenyl, alkynyl, perfluoroalkyl, F, Cl, Br, R10Oxe2x80x94, R1lS(O)mxe2x80x94, R10C(O)NR10xe2x80x94, (R10)2NC(O)xe2x80x94, R102Nxe2x80x94C(NR10)xe2x80x94, CN, NO2, R10C(O)xe2x80x94, N3, xe2x80x94N(R102, or R11OC(O)NR10xe2x80x94, and
c) C1-C6 alkyl unsubstituted or substituted by perfluoroalkyl, F, Cl, Br, R10Oxe2x80x94, R11S(O)mxe2x80x94, R10C(O)NR10xe2x80x94, (R10)2NC(O)xe2x80x94, R102Nxe2x80x94C(NR10)xe2x80x94, CN, R10C(O)xe2x80x94, N3, xe2x80x94N(R102, or R11OC(O)NR10xe2x80x94;
R10 is independently selected from hydrogen, C1-C6 alkyl, benzyl and aryl;
R11 is independently selected from C1-C6 alkyl and aryl;
A1 and A2 are independently selected from: a bond, xe2x80x94CHxe2x95x90CHxe2x80x94, xe2x80x94Cxe2x95x90Cxe2x80x94, xe2x80x94C(O)xe2x80x94, xe2x80x94C(O)NR10xe2x80x94, xe2x80x94NR10C(O)xe2x80x94, O, xe2x80x94N(R10)xe2x80x94, xe2x80x94S(O)2N(R10)xe2x80x94, xe2x80x94N(R10)S(O)2xe2x80x94, or S(O)m;
A3 is selected from: xe2x80x94C(O)xe2x80x94, xe2x80x94C(O)NR10xe2x80x94, xe2x80x94C(O)Oxe2x80x94, S(O)m or a bond;
A4 is selected from: bond, xe2x80x94Oxe2x80x94and xe2x80x94NR10xe2x80x94;
G is H2 or O, provided that G is not H2, if A3 is a bond;
V is selected from:
a) hydrogen,
b) heterocycle,
c) aryl,
d) C3-C20 alkyl wherein from 0 to 4 carbon atoms are replaced with a heteroatom selected from O, S, and N, and
e) C2-C20 alkenyl, provided that V is not hydrogen if A1 is S(O)m and V is not hydrogen if Al is a bond, n is 0 and A2 is S(O)m;
W is a heterocycle;
Z is an unsubstituted or substituted multicyclic ring, wherein the substituted multicyclic ring is substituted with one or two moieties selected from the following:
a) C1-4 alkoxy,
b) NR6R7,
c) C3-6 cycloalkyl,
d) xe2x80x94NR6C(O)R7,
e) HO,
f) xe2x80x94S(O)mR6a,
g) halogen,
h) perfluoroalkyl, and
i) C1-4 alkyl;
m is 0, 1 or 2;
n is 0, 1, 2, 3 or 4;
p is 0, 1, 2, 3 or 4;
q is 1 or 2;
r is 0 to 5, provided that r is 0 when V is hydrogen;
s is 0 or 1;
t is 0 or 1;
u is 4 or 5; and
v is 0, 1, 2 or 3;
or the pharmaceutically acceptable salts thereof
In a preferred embodiment of this invention, the inhibitors of prenyl-protein transferase are illustrated by the formula A: 
wherein:
R1a is independently selected from: hydrogen or C1-C6 alkyl;
R1b is independently selected from:
a) hydrogen,
b) aryl, heterocycle, cycloalkyl, R10Oxe2x80x94, xe2x80x94N(R10)2 or C2-C6 alkenyl,
c) unsubstituted or substituted C1-C6 alkyl wherein the substitutent on the substituted C1-C6 alkyl is selected from unsubstituted or substituted aryl, heterocycle, cycloalkyl, alkenyl, R10Oxe2x80x94 and xe2x80x94N(R10)2;
R1c is independently selected from:
a) hydrogen,
b) R10Oxe2x80x94, R10C(O)NR10xe2x80x94, (R10)2NC(O)xe2x80x94, R102Nxe2x80x94C(NR10)xe2x80x94, CN, NO2, R10C(O)xe2x80x94, N3, xe2x80x94N(R10)2 or R11OC(O)NR10xe2x80x94,
c) unsubstituted or substituted C1-C6 alkyl wherein the substitutent on the substituted C1-C6 alkyl is selected from R10Oxe2x80x94, R10C(O)NR10xe2x80x94, (R10)2NC(O)xe2x80x94, R102Nxe2x80x94C(NR10)xe2x80x94, CN, R10C(O)xe2x80x94, N3, xe2x80x94N(R10)2 and R11OC(O)xe2x80x94NR10xe2x80x94;or two R1cs on the same carbon are combined with that carbon to form a C4-C6 cycloalkyl;
R3 and R4 are independently selected from H and CH3;
R2 is H; 
xe2x80x83or C1-5 alkyl, unbranched or branched, unsubstituted or substituted with one or more of:
1) aryl,
2) heterocycle,
3) OR6,
4) SR6a, SO2R6a, or
5) 
xe2x80x83and any two of R2, R3, R4, and R5 are optionally attached to the same carbon atom;
R6 and R7 are independently selected from: H; C1-4 alkyl, C3-6 cycloalkyl, aryl, heterocycle, unsubstituted or substituted with:
a) C1-4 alkoxy,
b) halogen, or
c) aryl or heterocycle;
R6a is selected from: C1-4 alkyl or C3-6 cycloalkyl, unsubstituted or substituted with:
a) C1-4 alkoxy,
b) halogen, or
c) aryl or heterocycle;
R8 is independently selected from:
a) hydrogen,
b) C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 perfluoroalkyl, F, Cl, R10Oxe2x80x94, R10C(O)NR10xe2x80x94, CN, NO2, (R10)2Nxe2x80x94C(NR10)xe2x80x94, R10C(O)xe2x80x94, xe2x80x94N(R102, or R11OC(O)NR10xe2x80x94, and
c) C1-C6 alkyl substituted by C1-C6 perfluoroalkyl, R10Oxe2x80x94, R10C(O)NR10xe2x80x94, (R10)2Nxe2x80x94C(NR10)xe2x80x94, R10C(O)xe2x80x94, xe2x80x94N(R102, or R11OC(O)NR10xe2x80x94;
R9 is selected from:
a) hydrogen,
b) C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 perfluoroalkyl, F, Cl, R10Oxe2x80x94, R11S(O)mxe2x80x94, R10C(O)NR10xe2x80x94, CN, NO2, (R10)2Nxe2x80x94C(NR10)xe2x80x94, R10C(O)xe2x80x94, xe2x80x94N(R102, or R10C(O)NR10xe2x80x94, and
c) C1-C6 alkyl unsubstituted or substituted by C1-C6 perfluoroalkyl, F, Cl, R10Oxe2x80x94, R11S(O)mxe2x80x94, R10C(O)NR10xe2x80x94, CN, (R10)2Nxe2x80x94C(NR10)xe2x80x94, R10C(O)xe2x80x94, xe2x80x94N(R102, or R11OC(O)NR10xe2x80x94;
R10 is independently selected from hydrogen, C1-C6 alkyl, benzyl and aryl;
R11 is independently selected from C1-C6 alkyl and aryl;
A1 and A2 are independently selected from: a bond, xe2x80x94CHxe2x95x90CHxe2x80x94, xe2x80x94Cxe2x89xa1Cxe2x80x94, xe2x80x94C(O)xe2x80x94, xe2x80x94C(O)NR10xe2x80x94, O, xe2x80x94N(R10)xe2x80x94, or S(O)m;
A3 is selected from: xe2x80x94C(O)xe2x80x94, xe2x80x94C(O)NR10xe2x80x94, xe2x80x94C(O)Oxe2x80x94, S(O)m or a bond;
A4 is selected from: bond, xe2x80x94Oxe2x80x94and xe2x80x94NR10xe2x80x94;
G is H2 or O, provided that G is not H2, if A3 is a bond;
V is selected from:
a) hydrogen,
b) heterocycle selected from pyrrolidinyl, imidazolyl, pyridinyl, thiazolyl, pyridonyl, 2-oxopiperidinyl, indolyl, quinolinyl, isoquinolinyl, and thienyl,
c) aryl,
d) C1-C20 alkyl wherein from 0 to 4 carbon atoms are replaced with a a heteroatom selected from O, S, and N, and
e) C2-C20 alkenyl, and provided that V is not hydrogen if A1 is S(O)m and V is not hydrogen if Al is a bond, n is 0 and A2 is S(O)m;
W is a heterocycle selected from pyrrolidinyl, imidazolyl, pyridinyl, thiazolyl, pyridonyl, 2-oxopiperidinyl, indolyl, quinolinyl, or isoquinolinyl;
Z is an unsubstituted or substituted C7-C10 multicyclic alkyl ring, wherein the substituted C7-C10 multicyclic alkyl ring is substituted with one or two moieties selected from the following:
a) C1-4 alkoxy,
b) NR6R7,
c) C3-6 cycloalkyl,
d) xe2x80x94NR6C(O)R7,
e) HO,
f) xe2x80x94S(O)mR6a,
g) halogen,
h) perfluoroalkyl, and
i) C1-4 alkyl;
m is 0, 1 or 2;
n is 0, 1, 2, 3 or 4;
p is 0, 1, 2, 3 or 4;
r is 0 to 5, provided that r is 0 when V is hydrogen;
s is 0 or 1;
t is 0 or 1; and
v is 0, 1, 2 or 3; provided that v is not 0 if A3 is a bond;
or the pharmaceutically acceptable salts thereof.
A preferred embodiment of the compounds of this invention are illustrated by the formula B: 
wherein:
R1a and R1b are independently selected from:
a) hydrogen,
b) aryl, heterocycle, cycloalkyl, R10Oxe2x80x94, xe2x80x94N(R10)2 or C2-C6 alkenyl,
c) C1-C6 alkyl unsubstituted or substituted by aryl, heterocycle, cycloalkyl, alkenyl, R10Oxe2x80x94, or xe2x80x94N(R10)2;
R1c is independently selected from:
a) hydrogen,
b) R10Oxe2x80x94, R10C(O)NR10xe2x80x94, (R10)2NC(O)xe2x80x94, R102Nxe2x80x94C(NR10)xe2x80x94, CN, NO2, R10C(O)xe2x80x94, N3, xe2x80x94N(R10)2 or R11OC(O)NR10xe2x80x94,
c) unsubstituted or substituted C1-C6 alkyl wherein the substitutent on the substituted C1-C6 alkyl is selected from R10Oxe2x80x94, R10C(O)NR10xe2x80x94, (R10)2NC(O)xe2x80x94, R102Nxe2x80x94C(NR10)xe2x80x94, CN, R10C(O)xe2x80x94, N3, xe2x80x94N(R10)2 and R11OC(O)xe2x80x94NR10xe2x80x94;or two R1cs on the same carbon are combined with that carbon to form a C4-C6 cycloalkyl;
R3 is selected from H and CH3;
R2 is selected from H; 
xe2x80x83or C1-5 alkyl, unbranched or branched, unsubstituted or substituted with one or more of:
1) aryl,
2) heterocycle,
3) OR6,
4) SR6a, SO2R6a, or 
xe2x80x83and R2 and R3 are optionally attached to the same carbon atom;
R6 and R7 are independently selected from: H; C1-4 alkyl, C3-6 cycloalkyl, aryl, heterocycle, unsubstituted or substituted with:
a) C1-4 alkoxy,
b) halogen, or
c) aryl or heterocycle;
R6a is selected from: C1-4 alkyl or C3-6 cycloalkyl,unsubstituted or substituted with:
a) C1-4 alkoxy,
b) halogen, or
c) aryl or heterocycle;
R8 is independently selected from:
a) hydrogen,
b) C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 perfluoroalkyl, F, Cl, R10Oxe2x80x94, R10C(O)NR10xe2x80x94, CN, NO2, (R10)2Nxe2x80x94C(NR10)xe2x80x94, R10C(O)xe2x80x94, xe2x80x94N(R102, or R11OC(O)NR10xe2x80x94, and
c) C1-C6 alkyl substituted by C1-C6 perfluoroalkyl, R10Oxe2x80x94, R10C(O)NR10xe2x80x94, (R10)2Nxe2x80x94C(NR10)xe2x80x94, R10C(O)xe2x80x94, xe2x80x94N(R102, or R11OC(O)NR10xe2x80x94;
R9a is hydrogen or methyl;
R10 is independently selected from hydrogen, C1-C6 alkyl, benzyl and aryl;
R11 is independently selected from C1-C6 alkyl and aryl;
A1 and A2 are independently selected from: a bond, xe2x80x94CHxe2x95x90CHxe2x80x94, xe2x80x94Cxe2x89xa1Cxe2x80x94, xe2x80x94C(O)xe2x80x94, xe2x80x94C(O)NR10xe2x80x94, O, xe2x80x94N(R10)xe2x80x94, or S(O)m;
A3 is selected from: xe2x80x94C(O)xe2x80x94, xe2x80x94C(O)NR10xe2x80x94, xe2x80x94C(O)Oxe2x80x94 or S(O)m;
A4 is selected from: bond, xe2x80x94Oxe2x80x94and xe2x80x94NR10xe2x80x94;
V is selected from:
a) hydrogen,
b) heterocycle selected from pyrrolidinyl, imidazolyl, pyridinyl, thiazolyl, pyridonyl, 2-oxopiperidinyl, indolyl, quinolinyl, isoquinolinyl, and thienyl,
c) aryl,
d) C1-C20 alkyl wherein from 0 to 4 carbon atoms are replaced with a a heteroatom selected from O, S, and N, and
e) C2-C20 alkenyl, and provided that V is not hydrogen if A1 is S(O)m and V is not hydrogen if A1 is a bond, n is 0 and A2 is S(O)m;
Z is an unsubstituted or substituted C7-C10 multicyclic alkyl ring, wherein the substituted C7-C10 multicyclic alkyl ring is substituted with one or two moieties selected from the following:
a) C1-4 alkoxy,
b) NR6R7,
c) C3-6 cycloalkyl,
d) xe2x80x94NR6C(O)R7,
e) HO,
f) xe2x80x94S(O)mR6a,
g) halogen,
h) perfluoroalkyl, and
i) C1-4 alkyl;
C7-C10 multicyclic alkyl ring is selected from: 
m is 0, 1 or 2;
n is 1, 2, 3 or 4;
p is 0, 1, 2, 3 or 4;
r is 0 to 5, provided that r is 0 when V is hydrogen; and
v is 0, 1, 2 or 3; provided that v is not 0 if A3 is a bond;
or the pharmaceutically acceptable salts thereof.
Another preferred embodiment of the compounds of this invention are illustrated by the formula C: 
wherein:
R1a and R1b are independently selected from:
a) hydrogen,
b) aryl, heterocycle, cycloalkyl, R10Oxe2x80x94, xe2x80x94N(R10)2 or C2-C6 alkenyl,
c) C1-C6 alkyl unsubstituted or substituted by aryl, heterocycle, cycloalkyl, alkenyl, R10Oxe2x80x94, or xe2x80x94N(R10)2;
R1c is independently selected from:
a) hydrogen,
b) R10Oxe2x80x94, R10C(O)NR10xe2x80x94, (R10)2NC(O)xe2x80x94, R102Nxe2x80x94C(NR10)xe2x80x94, CN, NO2, R10C(O)xe2x80x94, N3, xe2x80x94N(R10)2 or R11OC(O)NR10xe2x80x94,
c) unsubstituted or substituted C1-C6 alkyl wherein the substitutent on the substituted C1-C6 alkyl is selected from R10Oxe2x80x94, R10C(O)NR10xe2x80x94, (R10)2NC(O)xe2x80x94, R102Nxe2x80x94C(NR10)xe2x80x94, CN, R10C(O)xe2x80x94, N3, xe2x80x94N(RI0)2 and R11OC(O)xe2x80x94NR10xe2x80x94;or two R1cs on the same carbon are combined with that carbon to form a C4-C6 cycloalkyl;
R3 is selected from H and CH3;
R2 is selected from H; 
xe2x80x83or C1-5 alkyl, unbranched or branched, unsubstituted or substituted with one or more of:
1) aryl,
2) heterocycle,
3) OR6,
4) SR6a, SO2R6a, or
5) 
xe2x80x83and R2 and R3 are optionally attached to the same carbon atom;
R6 and R7 are independently selected from: H; C1-4 alkyl, C3-6 cycloalkyl, aryl, heterocycle, unsubstituted or substituted with:
a) C1-4alkoxy,
b) halogen, or
c) aryl or heterocycle;
R6a is selected from: C1-4 alkyl or C3-6 cycloalkyl, unsubstituted or substituted with:
a) C1-4 alkoxy,
b) halogen, or
c) aryl or heterocycle;
R8 is independently selected from:
a) hydrogen,
b) C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 perfluoroalkyl, F, Cl, R10Oxe2x80x94, R10C(O)NR10xe2x80x94, CN, NO2, (R10)2Nxe2x80x94C(NR10)xe2x80x94, R10C(O)xe2x80x94, xe2x80x94N(R10)2, or R11OC(O)NR10xe2x80x94, and
c) C1-C6 alkyl substituted by C1-C6 perfluoroalkyl, R10Oxe2x80x94, R10C(O)NR10xe2x80x94, (R10)2Nxe2x80x94C(NR10)xe2x80x94, R10C(O)xe2x80x94, xe2x80x94N(R102, or R11OC(O)NR10xe2x80x94;
R9a is hydrogen or methyl;
R10 is independently selected from hydrogen, C1-C6 alkyl, benzyl and aryl;
R11 is independently selected from C1-C6 alkyl and aryl;
A1 and A2 are independently selected from: a bond, xe2x80x94CHxe2x95x90CHxe2x80x94, xe2x80x94Cxe2x89xa1Cxe2x80x94, xe2x80x94C(O)xe2x80x94, xe2x80x94C(O)NR10xe2x80x94, O, xe2x80x94N(R10)xe2x80x94, or S(O)m;
A3 is selected from: xe2x80x94C(O)xe2x80x94, xe2x80x94C(O)NR10xe2x80x94, xe2x80x94C(O)Oxe2x80x94 or S(O)m;
A4 is selected from: bond, xe2x80x94Oxe2x80x94and xe2x80x94NR10xe2x80x94;
V is selected from:
a) hydrogen,
b) heterocycle selected from pyrrolidinyl, imidazolyl, pyridinyl, thiazolyl, pyridonyl, 2-oxopiperidinyl, indolyl, quinolinyl, isoquinolinyl, and thienyl,
c) aryl,
d) C1-C20 alkyl wherein from 0 to 4 carbon atoms are replaced with a a heteroatom selected from O, S, and N, and
e) C2-C20 alkenyl, and provided that V is not hydrogen if A1 is S(O)m and V is not hydrogen if Al is a bond, n is 0 and A2 is S(O)m;
Z is an unsubstituted or substituted C7-C10 multicyclic alkyl ring, wherein the substituted C7-C10 multicyclic alkyl ring is substituted with one or two moieties selected from the following:
a) C1-4 alkoxy,
b) NR6R7,
c) C3-6 cycloalkyl,
d) xe2x80x94NR6C(O)R7,
e) HO,
f) xe2x80x94S(O)mR6a,
g) halogen,
h) perfluoroalkyl, and
i) C1-4 alkyl;
C7-C10 multicyclic alkyl ring is selected from: 
xe2x80x83m is 0, 1 or 2;
n is 0, 1, 2, 3 or 4;
p is 0, 1, 2, 3 or 4;
r is 0 to 5, provided that r is 0 when V is hydrogen; and
v is 0, 1, 2 or 3; provided that v is not 0 if A3 is a bond;
or the pharmaceutically acceptable salts thereof.
A further embodiment of the compounds of this invention is illustrated by the formula D: 
wherein:
R1a and R1b are independently selected from:
a) hydrogen,
b) aryl, heterocycle, cycloalkyl, R10Oxe2x80x94, xe2x80x94N(R10)2 or C2-C6 alkenyl,
c) C1-C6 alkyl unsubstituted or substituted by aryl, heterocycle, cycloalkyl, alkenyl, R10Oxe2x80x94, or xe2x80x94N(R10)2;
R1c is independently selected from:
a) hydrogen,
b) R10Oxe2x80x94, R10C(O)NR10xe2x80x94, (R10)2NC(O)xe2x80x94, R102Nxe2x80x94C(NR10)xe2x80x94, CN, NO2, R10C(O)xe2x80x94, N3, xe2x80x94N(R10)2 or R11OC(O)NR10xe2x80x94,
c) unsubstituted or substituted C1-C6 alkyl wherein the substitutent on the substituted C1-C6 alkyl is selected from R10Oxe2x80x94, R10C(O)NR10xe2x80x94, (R10)2NC(O)xe2x80x94, R102Nxe2x80x94C(NR10)xe2x80x94, CN, R10C(O)xe2x80x94, N3, xe2x80x94N(R10)2 and R11OC(O)xe2x80x94NR10xe2x80x94;
R3 is selected from H and CH3; 
R2 is selected from H; O or C1-5 alkyl, unbranched or branched, unsubstituted or substituted with one or more of:
1) aryl,
2) heterocycle,
3) OR6,
4) SR6a, SO2R6a, or
5) 
xe2x80x83and R2 and R3 are optionally attached to the same carbon atom;
R6 and R7 are independently selected from: H; C1-4 alkyl, C3-6 cycloalkyl, aryl, heterocycle, unsubstituted or substituted with:
a) C1-4 alkoxy,
b) halogen, or
c) aryl or heterocycle;
R6a is selected from: C1-4 alkyl or C3-6 cycloalkyl, unsubstituted or substituted with:
a) C1-4 alkoxy,
b) halogen, or
c) aryl or heterocycle;
R8 is independently selected from:
a) hydrogen,
b) C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 perfluoroalkyl, F, Cl, R10Oxe2x80x94, R10C(O)NR10xe2x80x94, CN, NO2, (R10)2Nxe2x80x94C(NR10)xe2x80x94, R10C(O)xe2x80x94, xe2x80x94N(R102, or R11OC(O)NR10xe2x80x94, and
c) C1-C6 alkyl substituted by C1-C6 perfluoroalkyl, R10Oxe2x80x94, R10C(O)NR10xe2x80x94, (R10)2Nxe2x80x94C(NR10)xe2x80x94, R10C(O)xe2x80x94, xe2x80x94N(R10)2, or R11OC(O)NR10xe2x80x94;
R9a is hydrogen or methyl;
R10 is independently selected from hydrogen, C1-C6 alkyl, benzyl and aryl;
R11 is independently selected from C1-C6 alkyl and aryl;
A1 is selected from: a bond, xe2x80x94CHxe2x95x90CHxe2x80x94, xe2x80x94Cxe2x95x90Cxe2x80x94, xe2x80x94C(O)xe2x80x94, xe2x80x94C(O)NR10xe2x80x94, O, xe2x80x94N(R10)xe2x80x94, or S(O)m;
A3 is selected from: xe2x80x94C(O)xe2x80x94, xe2x80x94C(O)NR10xe2x80x94 or xe2x80x94C(O)Oxe2x80x94;
A4 is selected from: bond and xe2x80x94Oxe2x80x94;
V is selected from:
a) heterocycle selected from pyridinyl and quinolinyl, and
b) aryl;
Z is an unsubstituted or substituted C7-C10 multicyclic alkyl ring, wherein the substituted C7-C10 multicyclic alkyl ring is substituted with one or two moieties selected from the following:
a) C1-4 alkoxy,
b) NR6R7,
c) C3-6 cycloalkyl,
d) xe2x80x94NR6C(O)R7,
e) HO,
f) xe2x80x94S(O)mR6a,
g) halogen,
h) perfluoroalkyl, and
i) C1-4 alkyl;
C7-C10 multicyclic alkyl ring is selected from: 
m is 0, 1 or 2;
n is 0, 1, 2, 3 or 4;
p is 0, 1, 2, 3 or 4;
r is 0 to 5, and
v is 0, 1, 2 or 3;
or the pharmaceutically acceptable salts thereof.
Another embodiment of the compounds of this invention is illustrated by the formula E: 
wherein:
R1a and R1b are independently selected from:
a) hydrogen,
b) aryl, heterocycle, cycloalkyl, R10Oxe2x80x94, xe2x80x94N(R10)2 or C2-C6 alkenyl,
c) C1-C6 alkyl unsubstituted or substituted by aryl, heterocycle, cycloalkyl, alkenyl, R10Oxe2x80x94, or xe2x80x94N(R10)2;
R1c is independently selected from:
a) hydrogen,
b) R10Oxe2x80x94, R10C(O)NR10xe2x80x94, (R10)2NC(O)xe2x80x94, R102Nxe2x80x94C(NR10)xe2x80x94, CN, NO2, R10C(O)xe2x80x94, N3, xe2x80x94N(R10)2 or R11OC(O)NR10xe2x80x94,
c) unsubstituted or substituted C1-C6 alkyl wherein the substitutent on the substituted C1-C6 alkyl is selected from R10Oxe2x80x94, R10C(O)NR10xe2x80x94, (R10)2NC(O)xe2x80x94, R102Nxe2x80x94C(NR10)xe2x80x94, CN, R10C(O)xe2x80x94, N3, xe2x80x94N(R10)2 and R11OC(O)xe2x80x94NR10xe2x80x94;
R3 is selected from H and CH3;
R2 is selected from H; 
xe2x80x83or C1-5 alkyl, unbranched or branched, unsubstituted or substituted with one or more of:
1) aryl,
2) heterocycle,
3) OR6,
4) SR6a, SO2R6a, or
5) 
xe2x80x83and R2 and R3 are optionally attached to the same carbon atom;
R6 and R7 are independently selected from: H; C1-4 alkyl, C3-6 cycloalkyl, aryl, heterocycle, unsubstituted or substituted with:
a) C1-4alkoxy,
b) halogen, or
c) aryl or heterocycle;
R6a is selected from: C1-4 alkyl or C3-6 cycloalkyl, unsubstituted or substituted with:
a) C1-4 alkoxy,
b) halogen, or
c) aryl or heterocycle;
R8 is independently selected from:
a) hydrogen,
b) C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 perfluoroalkyl, F, Cl, R10Oxe2x80x94, R10C(O)NR10xe2x80x94, CN, NO2, (R10)2Nxe2x80x94C(NR10)xe2x80x94, R10C(O)xe2x80x94, xe2x80x94N(R10)2, or R11OC(O)NR10xe2x80x94, and
c) C1-C6 alkyl substituted by C1-C6 perfluoroalkyl, R10Oxe2x80x94, R10C(O)NR10xe2x80x94, (R10)2Nxe2x80x94C(NR10)xe2x80x94, R10C(O)xe2x80x94, xe2x80x94N(R10)2, or R11OC(O)NR10xe2x80x94;
R9a is hydrogen or methyl;
R10 is independently selected from hydrogen, C1-C6 alkyl, benzyl and aryl;
R11 is independently selected from C1-C6 alkyl and aryl;
A1 is selected from: a bond, xe2x80x94CHxe2x95x90CHxe2x80x94, xe2x80x94Cxe2x89xa1Cxe2x80x94, xe2x80x94C(O)xe2x80x94, xe2x80x94C(O)NR10xe2x80x94, O, xe2x80x94N(R10)xe2x80x94, or S(O)m;
A3 is selected from: xe2x80x94C(O)xe2x80x94, xe2x80x94C(O)NR10xe2x80x94 or xe2x80x94C(O)Oxe2x80x94;
A4 is selected from: bond and xe2x80x94Oxe2x80x94;
V is selected from:
a) heterocycle selected from pyridinyl and quinolinyl, and
b) aryl;
Z is an unsubstituted or substituted C7-C10 multicyclic alkyl ring, wherein the substituted C7-C10 multicyclic alkyl ring is substituted with one or two moieties selected from the following:
a) C1-4 alkoxy,
b) NR6R7,
c) C3-6 cycloalkyl,
d) xe2x80x94NR6C(O)R7,
e) HO,
f) xe2x80x94S(O)mR6a,
g) halogen,
h) perfluoroalkyl, and
i) C1-4 alkyl;
C7-C10 multicyclic alkyl ring is selected from: 
xe2x80x83
m is 0, 1 or 2;
n is 0, 1, 2, 3 or 4;
p is 0, 1, 2, 3 or 4;
r is 0 to 5, and
v is 0, 1, 2 or 3;
or the pharmaceutically acceptable salts thereof.
A still further embodiment of the compounds of this invention is illustrated by the formula F: 
wherein:
R1b is independently selected from:
a) hydrogen,
b) aryl, heterocycle, cycloalkyl, R10Oxe2x80x94, xe2x80x94N(R10)2 or C2-C6 alkenyl,
c) C1-C6 alkyl unsubstituted or substituted by aryl, heterocycle, cycloalkyl, alkenyl, R10Oxe2x80x94, or xe2x80x94N(R10)2;
R1c is independently selected from:
a) hydrogen,
b) R10Oxe2x80x94, R10C(O)NR10xe2x80x94, (R10)2NC(O)xe2x80x94, R102Nxe2x80x94C(NR10)xe2x80x94, CN, NO2, R10C(O)xe2x80x94, N3, xe2x80x94N(R10)2 or R11OC(O)NR10xe2x80x94,
c) unsubstituted or substituted C1-C6 alkyl wherein the substitutent on the substituted C1-C6 alkyl is selected from R10Oxe2x80x94, R10C(O)NR10xe2x80x94, (R10)2NC(O)xe2x80x94, R102Nxe2x80x94C(NR10)xe2x80x94, CN, R10C(O)xe2x80x94, N3, xe2x80x94N(R10)2 and R11OC(O)xe2x80x94NR10xe2x80x94;
R3 is selected from H and CH3;
R2 is selected from H; 
xe2x80x83or C1-5 alkyl, unbranched or branched, unsubstituted or su tituted with one or more of:
1) aryl,
2) heterocycle,
3) OR6,
4) SR6a, SO2R6a, or
5) 
xe2x80x83and R2 and R3 are optionally attached to the same carbon atom;
R6 and R7 are independently selected from: H; C1-4 alkyl, C3-6 cycloalkyl, aryl, heterocycle, unsubstituted or substituted with:
a) C1-4 alkoxy,
b) halogen, or
c) aryl or heterocycle;
R6a is selected from: C1-4 alkyl or C3-6 cycloalkyl, unsubstituted or substituted with:
a) C1-4 alkoxy,
b) halogen, or
c) aryl or heterocycle;
R8 is independently selected from:
a) hydrogen,
b) C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 perfluoroalkyl, F, Cl, R10Oxe2x80x94, R10C(O)NR10xe2x80x94, CN, NO2, (R10)2Nxe2x80x94C(NR10)xe2x80x94, R10C(O)xe2x80x94, xe2x80x94N(R10)2, or R11OC(O)NR10xe2x80x94, and
c) C1-C6 alkyl substituted by C1-C6 perfluoroalkyl, R10Oxe2x80x94, R10C(O)NR10xe2x80x94, (R10)2Nxe2x80x94C(NR10)xe2x80x94, R10C(O)xe2x80x94, xe2x80x94N(R10)2, or R11OC(O)NR10xe2x80x94;
R9a is hydrogen or methyl;
R10 is independently selected from hydrogen, C1-C6 alkyl, benzyl and aryl;
R11 is independently selected from C1-C6 alkyl and aryl;
A3 is selected from: xe2x80x94C(O)xe2x80x94, xe2x80x94C(O)NR10xe2x80x94 or xe2x80x94C(O)Oxe2x80x94;
A4 is selected from: bond and xe2x80x94Oxe2x80x94;
Z is an unsubstituted or substituted C7-C10 multicyclic alkyl ring, wherein the substituted C7-C10 multicyclic alkyl ring is substituted with one or two moieties selected from the following:
a) C1-4 alkoxy,
b) NR6R7,
c) C3-6 cycloalkyl,
d) xe2x80x94NR6C(O)R7,
e) HO,
f) xe2x80x94S(O)mR6a,
g) halogen,
h) perfluoroalkyl, and
i) C1-4 alkyl;
C7-C10 multicyclic alkyl ring is selected from: 
m is 0, 1 or 2;
p is 1, 2 or 3;
r is 0 to 5, and
v is 0, 1, 2 or 3;
or the pharmaceutically acceptable salts thereof
Another further embodiment of the compounds of this invention is illustrated by the formula G: 
wherein:
R1b is independently selected from:
a) hydrogen,
b) aryl, heterocycle, cycloalkyl, R10Oxe2x80x94, xe2x80x94N(R10)2 or C2-C6 alkenyl,
c) C1-C6 alkyl unsubstituted or substituted by aryl, heterocycle, cycloalkyl, alkenyl, R10Oxe2x80x94, or xe2x80x94N(R10)2;
R1c is independently selected from:
a) hydrogen,
b) R10Oxe2x80x94, R10C(O)NR10xe2x80x94, (R10)2NC(O)xe2x80x94, R102Nxe2x80x94C(NR10)xe2x80x94, CN, NO2, R10C(O)xe2x80x94, N3, xe2x80x94N(R10)2 or R11OC(O)NR10xe2x80x94,
c) unsubstituted or substituted C1-C6 alkyl wherein the substitutent on the substituted C1-C6 alkyl is selected from R10Oxe2x80x94, R10C(O)NR10xe2x80x94, (R10)2NC(O)xe2x80x94, R102Nxe2x80x94C(NR10)xe2x80x94, CN, R10C(O)xe2x80x94, N3, xe2x80x94N(R10)2 and R11OC(O)xe2x80x94NR10xe2x80x94;
R3 is selected from H and CH3;
R2 is selected from H; 
xe2x80x83or C1-5 alkyl, unbranched or branched, unsubstituted or substituted with one or more of:
1) aryl,
2) heterocycle,
3) OR6,
4) SR6a, SO2R6a, or
5) 
xe2x80x83and R2 and R3 are optionally attached to the same carbon atom;
R6 and R7 are independently selected from: H; C1-4 alkyl, C3-6 cycloalkyl, aryl, heterocycle, unsubstituted or substituted with:
a) C1-4 alkoxy,
b) halogen, or
c) aryl or heterocycle;
R6a is selected from: C1-4 alkyl or C3-6 cycloalkyl, unsubstituted or substituted with:
a) C1-4 alkoxy,
b) halogen, or
c) aryl or heterocycle;
R8 is independently selected from:
a) hydrogen,
b) C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 perfluoroalkyl, F, Cl, R10Oxe2x80x94, R10C(O)NR10xe2x80x94, CN, NO2, (R10)2Nxe2x80x94C(NR10)xe2x80x94, R10C(O)xe2x80x94, xe2x80x94N(R10)2, or R11OC(O)NR10xe2x80x94, and
c) C1-C6 alkyl substituted by C1-C6 perfluoroalkyl, R10Oxe2x80x94, RIxc2x0 C(O)NR10xe2x80x94, (R10)2Nxe2x80x94C(NR10)xe2x80x94, R10C(O)xe2x80x94, xe2x80x94N(R10)2, or R11OC(O)NR10xe2x80x94;
R9a is hydrogen or methyl;
R10 is independently selected from hydrogen, C1-C6 alkyl, benzyl and aryl;
R11 is independently selected from C1-C6 alkyl and aryl;
A3 is selected from: xe2x80x94C(O)xe2x80x94, xe2x80x94C(O)NR10xe2x80x94 or xe2x80x94C(O)Oxe2x80x94;
A4 is selected from: bond and xe2x80x94Oxe2x80x94;
Z is an unsubstituted or substituted C7-C10 multicyclic alkyl ring, wherein the substituted C7-C10 multicyclic alkyl ring is substituted with one or two moieties selected from the following:
a) C1-4 alkoxy,
b) NR6R7,
c) C3-6 cycloalkyl,
d) xe2x80x94NR6C(O)R7,
e) HO,
f) xe2x80x94S(O)mR6a,
g) halogen,
h) perfluoroalkyl, and
i) C1-4 alkyl;
C7-C10 multicyclic alkyl ring is selected from: 
m is 0, 1 or 2;
p is 1, 2 or 3;
r is 0 to 5, and
v is 0, 1, 2 or 3;
or the pharmaceutically acceptable salts thereof
Specific examples of compounds of this invention are as follows:
1-(4-Cyanobenzyl)-5-[1-(2-oxo-2-(adamant-1-yl)ethyl)-2-oxo-piperazin-4-yl-methyl]imidazole
R/S 1-(4-Cyanobenzyl)-5-[1-(2-hydroxy-2-(adamant-1-yl)ethyl)-2-oxo-piperazin-4-yl-methyl]imidazole
1-(4-Cyanobenzyl)-5-[1-(2-hydroxy-2-(adamant-1-yl)ethyl)-2-oxo-piperazin-4-yl-methyl]imidazole
1-(4-Cyanobenzyl)-5-[1-(2-acetyloxy-2-(adamant-1-yl)ethyl)-2-oxo-piperazin-4-yl-methyl]imidazole
1-[1-(4xe2x80x2-Cyanobenzyl)imidazol-5-ylmethyl] piperazine-4-(N-1-adamantyl)carboxamide
1-[1-(4xe2x80x2-Cyanobenzyl)imidazol-5-ylmethyl]-4-(N-1-adamantyl)carbonyl piperazine
1-[1-(4xe2x80x2-Cyanobenzyl)imidazol-5-ylmethyl]-4-[N-(1R)-(xe2x88x92)-10-camphorsulfonyl]piperazine
1-[1-(4xe2x80x2-Cyanobenzyl)imidazol-5-ylmethyl]-4-(1-adamantylmethyl) piperazine
1-(4-Cyanobenzyl)-5-[1-(2-(adamant-1-yl)ethyl)-2-oxo-piperazin-4-yl-methyl]imidazole
1-(4-Cyanobenzyl)-5-[1-(1-(adamant-1-yl)methyl)-2-oxo-piperazin-4-yl-methyl]imidazole
1-[1-(4xe2x80x2-Cyanobenzyl)imidazol-5-ylmethyl] piperazine-4-carboxylic acid (2-norbornane)methyl ester
1-[1-(4xe2x80x2-Cyanobenzyl)imidazol-5-ylmethyl]-piperazine-4-carboxylic acid (2-norbornane)methyl ester
1-[1-(4xe2x80x2-Cyanobenzyl)imidazol-5-ylmethyl] -4-(2-bicyclo-[2.2.2]-octylcarbonyl)piperazine
1-[1-(4xe2x80x2-Cyanobenzyl)imidazol-5-ylmethyl]-4-(2-norbornanecarbonyl)piperazine
1-[1-(4xe2x80x2-Cyanobenzyl)imidazol-5-ylmethyl]-4-cis/trans-(2,6,6-trimethylbicyclo[3.1.1]heptanecarbonyl)-piperazine
1-(4xe2x80x2-Cyanobenzyl)-2-methyl-imidazol-5-ylmethyl piperazine-4-(N-1-adamantyl)carboxamide
or the pharmaceutically acceptable salts or optical isomers thereof.
The compounds of the instant invention differ from previously disclosed piperazinone-containing and piperazine-containing compounds, (PCT Publ. No. WO 96/30343xe2x80x94Oct. 3, 1996; U.S. Pat. No. 5,856,326xe2x80x94Jan. 5, 1999; PCT Publ. No. WO 96/31501xe2x80x94Oct. 10, 1996; PCT Publ. No. WO 97/36593xe2x80x94Oct. 9, 1997; PCT Publ. No. WO 97/36592xe2x80x94Oct. 9, 1997) that were described as inhibitors of farnesyl-protein transferase (FPTase), in that, among other things, the instant compounds are dual inhibitors of farnesyl-protein transferase and geranylgeranyl-protein transferase type I (GGTase-I).
In one embodiment of the invention, the compounds are further characterized in that the inhibitory activity of the compounds against GGTase-I is greater than the inhibitory activity against FPTase. Preferably, the compounds of this embodiment of the instant invention inhibit FPTase in vitro Example 16) at an IC50 of less than 1 xcexcM and inhibit GGTase-I in vitro (Example 17) at an IC50 of less than 50 nM. Also preferably, the compounds of this embodiment of the instant invention inhibit the cellular processing of the Rap 1 protein (Example 22, Protocol C) at an EC50 of less than about 1 xcexcM. More preferably, the compounds of this embodiment of the instant invention inhibit the cellular processing of the Rapl protein (Example 22, Protocol C) at an EC50 of less than about 50 nM. Also more preferably, the ratio of the IC50 of the compounds of this embodiment of the instant invention for in vitro inhibition of FPTase to the IC50 of the compounds of the instant invention for in vitro inhibition of GGTase type I is greater than 25. Also more preferably, the ratio of the EC50 of the compounds of this embodiment of the instant invention for inhibition of the cellular processing of the hDJ protein (Example 21) to the EC50 of the compounds of the instant invention for inhibition of the cellular processing of the Rap 1 protein is about equal to or less than 1.
In a second embodiment of the compounds of the instant invention, the compounds are further characterized in that the inhibitory activity of the compounds against FPTase is greater than the inhibitory activity against GGTase-I. Preferably, the compounds of this second embodiment of the instant invention inhibit FPTase in vitro (Example 16) at an IC50 of less than 100 nM and inhibit GGTase-I in vitro (Example 17) at an IC50 of less than 5 xcexcM. Preferably, the compounds of this second embodiment of the instant invention inhibit the cellular processing of the hDJ protein (Example 21) at an EC50 of less than about 250 nM. Also preferably, the compounds of this second embodiment of the instant invention inhibit the cellular processing of the Rap 1 protein (Example 22, Protocol C) at an EC50 of less than about 10 xcexcM. More preferably, the compounds of this second embodiment of the instant invention inhibit the cellular processing of the Rap 1 protein (Example 22, Protocol C) at an EC50 of less than about 1 xcexcM. Also more preferably, the ratio of the IC50 of the compounds of this embodiment of the instant invention for in vitro inhibition of GGTase type I to the IC50 of the compounds of the instant invention for in vitro inhibition of FPTase is greater than 1 and less than 25. Also more preferably, the ratio of the EC50 of the compounds of this second embodiment of the instant invention for inhibition of the cellular processing of the hDJ protein (Example 21) to the EC50 of the compounds of the instant invention for inhibition of the cellular processing of the Rap 1 protein is between about 1 and about 100.
The compounds of the present invention may have asymmetric centers and occur as racemates, racemic mixtures, and as individual diastereomers, with all possible isomers, including optical isomers, being included in the present invention. When any variable (e.g. aryl, heterocycle, R1, R2 etc.) occurs more than one time in any constituent, its definition on each occurrence is independent at every other occurrence. Also, combinations of substituents/or variables are permissible only if such combinations result in stable compounds.
As used herein, xe2x80x9calkylxe2x80x9d is intended to include both branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms; xe2x80x9calkoxyxe2x80x9d represents an alkyl group of indicated number of carbon atoms attached through an oxygen bridge. xe2x80x9cHalogenxe2x80x9d or xe2x80x9chaloxe2x80x9d as used herein means fluoro, chloro, bromo and iodo.
As used herein, xe2x80x9ccycloalkylxe2x80x9d is intended to include monocyclic saturated aliphatic hydrocarbon groups having the specified number of carbon atoms. Examples of such cycloalkyl groups includes, but are not limited to, cyclopropyl, cyclobutyl, cyclohexyl, cycloheptyl and cyclooctyl.
As used herein, xe2x80x9carylxe2x80x9d is intended to mean any stable monocyclic or bicyclic carbon ring of up to 7 members in each ring, wherein at least one ring is aromatic. Examples of such aryl elements include phenyl, naphthyl, tetrahydronaphthyl, indanyl and biphenyl.
The term heterocycle or heterocyclic, as used herein, represents a stable 5- to 7-membered monocyclic or stable 8- to 11-membered bicyclic heterocyclic ring which is either saturated or unsaturated, and which consists of carbon atoms and from one to four heteroatoms selected from the group consisting of N, O, and S, and including any bicyclic group in which any of the above-defined heterocyclic rings is fused to a benzene ring. The term heterocycle or heterocyclic, as used herein, includes heteroaryl moieties. The heterocyclic ring may be attached at any heteroatom or carbon atom which results in the creation of a stable structure. Examples of such heterocyclic elements include, but are not limited to, azepinyl, benzimidazolyl, benzisoxazolyl, benzofurazanyl, benzopyranyl, benzothiopyranyl, benzofuryl, benzothiazolyl, benzothienyl, benzoxazolyl, chromanyl, cinnolinyl, dihydrobenzofuryl, dihydrobenzothienyl, dihydrobenzothiopyranyl, dihydrobenzothiopyranyl sulfone, furyl, imidazolidinyl, imidazolinyl, imidazolyl, indolinyl, indolyl, isochromanyl, isoindolinyl, isoquinolinyl, isothiazolidinyl, isothiazolyl, isothiazolidinyl, morpholinyl, naphthyridinyl, oxadiazolyl, 2-oxoazepinyl, oxazolyl, 2-oxopiperazinyl, 2-oxopiperdinyl, 2-oxopyrrolidinyl, piperidyl, piperazinyl, pyridyl, pyrazinyl, pyrazolidinyl, pyrazolyl, pyridazinyl, pyrimidinyl, pyrrolidinyl, pyrrolyl, quinazolinyl, quinolinyl, quinoxalinyl, tetrahydrofuryl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, thiamorpholinyl, thiamorpholinyl sulfoxide, thiazolyl, thiazolinyl, thienofuryl, thienothienyl, and thienyl.
As used herein, xe2x80x9cheteroarylxe2x80x9d is intended to mean any stable monocyclic or bicyclic carbon ring of up to 7 members in each ring, wherein at least one ring is aromatic and wherein from one to four carbon atoms are replaced by heteroatoms selected from the group consisting of N, O, and S. Examples of such heterocyclic elements include, but are not limited to, benzimid-azolyl, benzisoxazolyl, benzofurazanyl, benzopyranyl, benzo-thiopyranyl, benzofuryl, benzothiazolyl, benzothienyl, benzoxazolyl, chromanyl, cinnolinyl, dihydrobenzofuryl, dihydrobenzothienyl, dihydrobenzothiopyranyl, dihydro-benzothiopyranyl sulfone, furyl, imidazolyl, indolinyl, indolyl, isochromanyl, isoindolinyl, isoquinolinyl, isothiazolyl, naphthyridinyl, oxadiazolyl, pyridyl, pyrazinyl, pyrazolyl, pyridazinyl, pyrimidinyl, pyrrolyl, quinazolinyl, quinolinyl, quinoxalinyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, thiazolyl, thienofuryl, thienothienyl, and thienyl.
As used herein in the definition of R2 and R3, the term xe2x80x9cthe substituted groupxe2x80x9d intended to mean a substituted C1-8 alkyl, substituted C2-8 alkenyl, substituted C2-8 alkynyl, substituted aryl or substituted heterocycle from which the substituent(s) R2 and R3 are selected.
As used herein in the definition of R6, R6a, R7 and R7a, the substituted C1-8 alkyl, substituted C3-6 cycloalkyl, substituted aroyl, substituted aryl, substituted heteroaroyl, substituted arylsulfonyl, substituted heteroarylsulfonyl and substituted heterocycle include moieties containing from 1 to 3 substituents in addition to the point of attachment to the rest of the compound. Preferably, such substituents are selected from the group which includes but is not limited to F, Cl, Br, CF3, NH2, N(C1-C6 alkyl2, NO2, CN, (C1-C6 alkyl)Oxe2x80x94, xe2x80x94OH, (C1-C6 alkyl)S(O)mxe2x80x94, (C1-C6 alkyl)C(O)NHxe2x80x94, H2Nxe2x80x94C(NH)xe2x80x94, (C1-C6 alkyl)C(O)xe2x80x94, (C1-C6 alkyl)OC(O)xe2x80x94, N3, (C1-C6 alkyl)OC(O)NHxe2x80x94, phenyl, pyridyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, thienyl, furyl, isothiazolyl and C1-C20 alkyl.
As used herein, xe2x80x9cmulticyclic ringxe2x80x9d is intended to include polycyclic saturated and unsaturated aliphatic hydrocarbon groups which optionally contain 1-3 heteroatoms, selected from N, O and S. Examples of such multicyclic rings includes, but are not limited to: 
As used herein, xe2x80x9cmulticyclic alkyl ringxe2x80x9d is intended to include polycyclic saturated and unsaturated aliphatic hydrocarbon groups having the specified number of carbon atoms. Examples of such cycloalkyl groups includes, but are not limited to: 
When R2 and R3 are combined to formxe2x80x94(CH2)uxe2x80x94, and when two R1c son the same carbon are combined with that carbon to form a C4-C6 cycloalkyl, cyclic moieties are formed. Examples of such cyclic moieties include, but are not limited to: 
In addition, with respect to R2 and R3, such cyclic moieties may optionally include a heteroatom(s). Examples of such heteroatom-containing cyclic moieties include, but are not limited to: 
The moiety formed when, in the definition of R6, R7 and R7a, R6 and R7 or R7 and R7a are joined to form a ring, is illustrated by, but not limited to, the following: 
Lines drawn into the ring systems from substituents (such as from R2, R3, R4 etc.) represent that the indicated bond may be attached to any of the substitutable ring carbon atoms.
Preferably, R1a and R1b are independently selected from: hydrogen, xe2x80x94N(R102, R10C(O)NR10xe2x80x94 or unsubstituted or substituted C1-C6 alkyl wherein the substituent on the substituted C1-C6 alkyl is selected from unsubstituted or substituted phenyl, xe2x80x94N(R102, R10Oxe2x80x94 and R10C(O)NR10xe2x80x94.
Preferably, R2 is selected from: hydrogen, 
and an unsubstituted or substituted group, the group selected from C1-8 alkyl, C2-8 alkenyl and C2-8 alkynyl; wherein the substituted group is substituted with one or more of:
1) aryl or heterocycle,
2) OR6, and
3) SR6a, SO2R6a.
Preferably, R3 is selected from hydrogen and methyl.
Preferably, R4 is hydrogen.
Preferably, R6 and R7 are selected from: hydrogen, unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted aryl and unsubstituted or substituted C3-C6 cycloalkyl.
Preferably, R6a is unsubstituted or substituted C1-C6.
Preferably, R9 is hydrogen or methyl.
Preferably, R10 is selected from H, C1-C6 alkyl and benzyl.
Preferably, A1 and A2 are independently selected from: a bond, xe2x80x94C(O)NR10xe2x80x94, xe2x80x94NR10C(O)xe2x80x94, O, xe2x80x94N(R10)xe2x80x94, xe2x80x94S(O)2N(R10)xe2x80x94 and xe2x80x94N(R10)S(O)2xe2x80x94. Most preferably, A1 and A2 are a bond.
Preferably, A3 is selected from: xe2x80x94C(O)xe2x80x94, xe2x80x94C(O)NR10xe2x80x94 and xe2x80x94C(O)Oxe2x80x94.
Preferably, A4 is a bond.
Preferably, V is selected from heteroaryl and aryl. More preferably, V is phenyl.
Preferably, W is selected from imidazolyl, pyridinyl, thiazolyl, indolyl, quinolinyl, or isoquinolinyl. More preferably, W is imidazolyl and pyridyl.
Preferably, Z is a unsubstituted or substituted C7-C10 multicyclic alkyl ring.
Preferably, the C7-C10 multicyclic alkyl ring is selected from: 
Preferably, n and r are independently 0, 1, or 2.
Preferably p is 1, 2 or 3.
Preferably s is 0.
Preferably t is 1.
Preferably v is 0, 1 or 2.
Preferably, the moiety 
is selected from: 
Preferably, the moiety A1 (CR1a2)nA2(CR1a2)n is not a bond.
It is intended that the definition of any substituent or variable (e.g., R1a, R9, n, etc.) at a particular location in a molecule be independent of its definitions elsewhere in that molecule. Thus,xe2x80x94N(R10)2 represents xe2x80x94NHH, xe2x80x94NHCH3, xe2x80x94NHC2H5, etc. It is understood that substituents and substitution patterns on the compounds of the instant invention can be selected by one of ordinary skill in the art to provide compounds that are chemically stable and that can be readily synthesized by techniques known in the art, as well as those methods set forth below, from readily available starting materials.
The pharmaceutically acceptable salts of the compounds of this invention include the conventional non-toxic salts of the compounds of this invention as formed, e.g., from non-toxic inorganic or organic acids. For example, such conventional non-toxic salts include those derived from inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, nitric and the like: and the salts prepared from organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, sulfanilic, 2-acetoxy-benzoic, fumaric, toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, isethionic, trifluoroacetic and the like.
The pharmaceutically acceptable salts of the compounds of this invention can be synthesized from the compounds of this invention which contain a basic moiety by conventional chemical methods. Generally, the salts are prepared either by ion exchange chromatography or by reacting the free base with stoichiometric amounts or with an excess of the desired salt-forming inorganic or organic acid in a suitable solvent or various combinations of solvents.
Reactions used to generate the compounds of this invention are prepared by employing reactions as shown in the Schemes 1-21, in addition to other standard manipulations such as ester hydrolysis, cleavage of protecting groups, etc., as may be known in the literature or exemplified in the experimental procedures. Substituents R, Ra and Rb, as shown in the Schemes, represent the substituents R2, R3 and R4; however their point of attachment to the ring is illustrative only and is not meant to be limiting. Substituent Zxe2x80x2, as shown in the Schemes, represents the substiutent Z as defined hereinabove or a protected precursor thereof.
These reactions may be employed in a linear sequence to provide the compounds of the invention or they may be used to synthesize fragments which are subsequently joined by the alkylation reactions described in the Schemes.
Synopsis of Schemes 1-21:
The requisite intermediates are in some cases commercially available, or can be prepared according to literature procedures, for the most part. In Scheme 1, for example, the synthesis of 2-cycloalkylalkanoyl substituted piperazines is outlined. Boc-protected amino acids I, available commercially or by procedures known to those skilled in the art, can be coupled to N-benzyl amino acid esters using a variety of dehydrating agents such as DCC (dicyclohexycarbodiimide) or EDC.HCl (1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride) in a solvent such as methylene chloride, chloroform, dichloroethane, or dimethylformamide. The product II is then deprotected with acid, for example hydrogen chloride in chloroform or ethyl acetate, or trifluoroacetic acid in methylene chloride, and cyclized under weakly basic conditions to give the diketopiperazine III. Reduction of III with lithium aluminum hydride in refluxing ether gives the piperazine IV, which is protected as the Boc derivative V. The N-benzyl group can be cleaved under standard conditions of hydrogenation, e.g., 10% palladium on carbon at 60 psi hydrogen on a Parr apparatus for 24-48 h. The product VI can be reacted with a suitably substituted carboxylic acid to provide the piperazine VII; a final acid deprotection as previously described gives the intermediate VIII (Scheme 2). The intermediate VIII can itself be reductively alkylated with a variety of aldehydes, such as IX. The aldehydes can be prepared by standard procedures, such as that described by O. P. Goel, U. Krolls, M. Stier and S. Kesten in Organic Syntheses, 1988, 67, 69-75, from the appropriate amino acid (Scheme 3). The reductive alkylation can be accomplished at pH 5-7 with a variety of reducing agents, such as sodium triacetoxyborohydride or sodium cyanoborohydride in a solvent such as dichloroethane, methanol or dimethylformamide. The product X can be deprotected to give the final compounds XI with trifluoroacetic acid in methylene chloride. The final product XI is isolated in the salt form, for example, as a trifluoroacetate, hydrochloride or acetate salt, among others. The product diamine XI can further be selectively protected to obtain XII, which can subsequently be reductively alkylated with a second aldehyde to obtain XIII. Removal of the protecting group, and conversion to cyclized products such as the dihydroimidazole XV can be accomplished by literature procedures.
As shown in Scheme 4, the piperazine intermediate VIII can be reductively alkylated with other aldehydes such as 1-trityl-4-imidazolyl-carboxaldehyde or 1-trityl-4-imidazolyl-acetaldehyde, to give products such as XVI. The trityl protecting group can be removed from XVI to give XVII, or alternatively, XVI can first be treated with an alkyl halide then subsequently deprotected to give the alkylated imidazole XVIII. Alternatively, the intermediate VIII can be acylated or sulfonylated by standard techniques.
Incorporation of a hydroxyl moiety on the sidechain carbon alpha to the amide carbonyl of compounds of the formula XVIII can be accomplished as illustrated in Scheme 5. A suitably substituted primary alcohol XIX undergoes a one carbon homologation, via a Swern oxidation, nitrile addition and hydrolysis, to provide the substituted hydroxyacetic acid XX. The trifluoromethyl ketal is formed and reacted with the previously described protected piperazine VI to provide, following deprotection, the intermediate XXI. Intermediate XXI can undergo a variety of reactions at its unsubstituted nitrogen. For example, treatment of XXI with a suitably substituted imidazolylmethyl halide to provide the instant compound XXII.
Scheme 6 illustrates incorporation of a cycloalkylalkoxycarbonyl moiety onto the piperazine nitrogen. Thus a suitably substituted alcohol XXIII is reacted with nitrophenylchloroformate to provide the intermediate XXIV, which is reacted with a suitably substituted piperazine to provide the instant compound XXV. An analogous reaction sequence alternatively provides the corresponding aminocarbonyl substitution on the piperazine nitrogen, as shown in Scheme 7.
Scheme 8 illustrates the preparation of compounds analogous to compound XXXI wherein the alcohol utilized in the first step is a suitably substituted adamantanol. The scheme also illustrates the incorporation of an indole moiety for the substiutent W in place of the preferred benzylimidazolyl moiety.
Scheme 9 illustrates synthesis of an instant compound wherein a non-hydrogen R9b is incorporated in the instant compound. Thus, a readily available 4-substituted imidazole XXVI may be selectively iodinated to provide the 5-iodoimidazole XXVII. That imidazole may then be protected and coupled to a suitably substituted benzyl moiety to provide intermediate XXVIII. Attachment of the imidazolyl nitrogen via an ethyl linker to the piperazine nitrogen of intermediate XXI, described above, provides the instant compound XXIX.
Compounds of the instant invention wherein the A1(CR1a2)nA2(CR1a2)n linker is oxygen may be synthesized by methods known in the art, for example as shown in Scheme 10. The suitably substituted phenol XXX may be reacted with methyl N-(cyano)methanimidate to provide the 4-phenoxy-imidazole XXXI. After selective protection of one of the imidazolyl nitrogens, the intermediate XXXII can undergo alkylation reactions as described for the benzylimidazoles in Scheme 9.
If the piperazine VIII is reductively alkylated with an aldehyde which also has a protected hydroxyl group, such as XXXIII in Scheme 11, the protecting groups can be subsequently removed to unmask the hydroxyl group The Boc protected amino alcohol XXXIV can then be utilized to synthesize 2-aziridinyl-methylpiperazines such as XXXV.
5-Substituted piperazin-2-ones can be prepared as shown in Scheme 12. Reductive amination of Boc-protected amino aldehydes XXXVI (prepared from I as illustrated) gives rise to compound XXXVII. This is then reacted with bromoacetyl bromide under Schotten-Baumann conditions; ring closure is effected with a base such as sodium hydride in a polar aprotic solvent such as dimethylformamide to give XXXVIII. The carbamate protecting group is removed under acidic conditions such as trifluoroacetic acid in methylene chloride, or hydrogen chloride gas in methanol or ethyl acetate, and the resulting piperazine can then be carried on to final products as described in above.
The isomeric 3-substituted piperazin-2-ones can be prepared as described in Scheme 13. The imine formed from arylcarboxamides IXL and 2-aminoglycinal diethyl acetal (XL) can be reduced under a variety of conditions, including sodium triacetoxyborohydride in dichloroethane, to give the amine XLI. A suitably substituted amino acid I can be coupled to amine XLI under standard conditions, and the resulting amide XLII when treated with aqueous acid in tetrahydrofuran can cyclize to the unsaturated XLIII. Catalytic hydrogenation under standard conditions gives the requisite intermediate XLIV, which is elaborated to final products as described in above.
Reaction Scheme 14 provides an illustrative example of the synthesis of compounds of the instant invention wherein the substituents R2 and R3 are combined to form xe2x80x94(CH2)uxe2x80x94. For example, 1-aminocyclohexane-1-carboxylic acid XLV can be converted to the spiropiperazine XLVI essentially according to the procedures outlined in Schemes 1 and 2. The piperazine intermediate XLVI can be deprotected as before, and carried on to final products as described in Schemes 3-8. It is understood that reagents utilized to provide the imidazolylalkyl substituent may be readily replaced by other reagents well known in the art and readily available to provide other N-substituents on the piperazine.
Scheme 15 illustrates the use of an optionally substituted homoserine lactone XLVII to prepare a Boc-protected piperazinone XLVIII. Intermediate XLVIII may be deprotected and reductively alkylated or acylated as illustrated in the previous Schemes. Alternatively, the hydroxyl moiety of intermediate XLVIII may be mesylated and displaced by a suitable nucleophile, such as the sodium salt of ethane thiol, to provide an intermediate IL. Intermediate XLVIII may also be oxidized to provide the carboxylic acid on intermediate L, which can be utilized form an ester or amide moiety.
Amino acids of the general formula LI which have a sidechain not found in natural amino acids may be prepared by the reactions illustrated in Scheme 16 starting with the readily prepared imine LII.
Schemes 17-20 illustrate syntheses of suitably substituted aldehydes useful in the syntheses of the instant compounds wherein the variable W is present as a pyridyl moiety. Similar synthetic strategies for preparing alkanols that incorporate other heterocyclic moieties for variable W are also well known in the art. For example, Scheme 21 illustrates the preparation of the corresponding quinoline aldehyde. Scheme 22 depicts a general method for synthesizing a key intermediate useful in the preparation of a preferred embodiments of the instant invention wherein V is phenyl and W is imidazole. A piperazine moiety can be readily added to this benzyl-imidazole intermediate as set forth in Scheme 23. 
The instant compounds are useful as pharmaceutical agents for mammals, especially for humans. These compounds may be administered to patients for use in the treatment of cancer. Examples of the type of cancer which may be treated with the compounds of this invention include, but are not limited to, colorectal carcinoma, exocrine pancreatic carcinoma, myeloid leukemias and neurological tumors. Such tumors may arise by mutations in the ras genes themselves, mutations in the proteins that can regulate Ras activity (i.e., neurofibromin (NF-1), neu, src, ab1, 1ck, fyn) or by other mechanisms.
The compounds of the instant invention inhibit prenyl-protein transferase and the prenylation of the oncogene protein Ras. The instant compounds may also inhibit tumor angiogenesis, thereby affecting the growth of tumors (J. Rak et al. Cancer Research, 55: 4575-4580 (1995)). Such anti-angiogenesis properties of the instant compounds may also be useful in the treatment of certain forms of vision deficit related to retinal vascularization.
The compounds of this invention are also useful for inhibiting other proliferative diseases, both benign and malignant, wherein Ras proteins are aberrantly activated as a result of oncogenic mutation in other genes (i.e., the Ras gene itself is not activated by mutation to an oncogenic form) with said inhibition being accomplished by the administration of an effective amount of the compounds of the invention to a mammal in need of such treatment. For example, a component of NF-1 is a benign proliferative disorder.
The instant compounds may also be useful in the treatment of certain viral infections, in particular in the treatment of hepatitis delta and related viruses (J. S. Glenn et al. Science, 256:1331-1333 (1992).
The compounds of the instant invention are also useful in the prevention of restenosis after percutaneous transluminal coronary angioplasty by inhibiting neointimal formation (C. Indolfi et al. Nature medicine, 1:541-545(1995).
The instant compounds may also be useful in the treatment and prevention of polycystic kidney disease (D. L. Schaffner et al. American Journal of Pathology, 142:1051-1060 (1993) and B. Cowley, Jr. et al. FASEB Journal, 2:A3160 (1988)).
The instant compounds may also be useful for the treatment of fungal infections.
The instant compounds may also be useful as inhibitors of proliferation of vascular smooth muscle cells and therefore useful in the prevention and therapy of arteriosclerosis and diabetic vascular pathologies.
The compounds of this invention may be administered to mammals, preferably humans, either alone or, preferably, in combination with pharmaceutically acceptable carriers, excipients or diluents, in a pharmaceutical composition, according to standard pharmaceutical practice. The compounds can be administered orally or parenterally, including the intravenous, intramuscular, intraperitoneal, subcutaneous, rectal and topical routes of administration.
The pharmaceutical compositions containing the active ingredient may be in a form suitable for oral use, for example, as tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or elixirs. Compositions intended for oral use may be prepared according to any method known to the art for the manufacture of pharmaceutical compositions and such compositions may contain one or more agents selected from the group consisting of sweetening agents, flavoring agents, coloring agents and preserving agents in order to provide pharmaceutically elegant and palatable preparations. Tablets contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients which are suitable for the manufacture of tablets. These excipients may be for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, for example, microcrystalline cellulose, sodium crosscarmellose, corn starch, or alginic acid; binding agents, for example starch, gelatin, polyvinyl-pyrrolidone or acacia, and lubricating agents, for example, magnesium stearate, stearic acid or talc. The tablets may be uncoated or they may be coated by known techniques to mask the unpleasant taste of the drug or delay disintegration and absorption in the gastro-intestinal tract and thereby provide a sustained action over a longer period. For example, a water soluble taste masking material such as hydroxypropylmethyl-cellulose or hydroxy-propylcellulose, or a time delay material such as ethyl cellulose, cellulose acetate buryrate may be employed.
Formulations for oral use may also be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with water soluble carrier such as polyethyl-eneglycol or an oil medium, for example peanut oil, liquid paraffin, or olive oil.
Aqueous suspensions contain the active material in admixture with excipients suitable for the manufacture of aqueous suspensions. Such excipients are suspending agents, for example sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethyl-cellulose, sodium alginate, polyvinyl-pyrrolidone, gum tragacanth and gum acacia; dispersing or wetting agents may be a naturally-occurring phosphatide, for example lecithin, or condensation products of an alkylene oxide with fatty acids, for example polyoxyethylene stearate, or condensation products of ethylene oxide with long chain aliphatic alcohols, for example heptadecaethylene-oxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, for example polyethylene sorbitan monooleate. The aqueous suspensions may also contain one or more preservatives, for example ethyl, or n-propyl p-hydroxybenzoate, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents, such as sucrose, saccharin or aspartame.
Oily suspensions may be formulated by suspending the active ingredient in a vegetable oil, for example arachis oil, olive oil, sesame oil or coconut oil, or in mineral oil such as liquid paraffin. The oily suspensions may contain a thickening agent, for example beeswax, hard paraffin or cetyl alcohol. Sweetening agents such as those set forth above, and flavoring agents may be added to provide a palatable oral preparation. These compositions may be preserved by the addition of an anti-oxidant such as butylated hydroxyanisol or alpha-tocopherol.
Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide the active ingredient in admixture with a dispersing or wetting agent, suspending agent and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified by those already mentioned above. Additional excipients, for example sweetening, flavoring and coloring agents, may also be present. These compositions may be preserved by the addition of an anti-oxidant such as ascorbic acid.
The pharmaceutical compositions of the invention may also be in the form of an oil-in-water emulsions. The oily phase may be a vegetable oil, for example olive oil or arachis oil, or a mineral oil, for example liquid paraffin or mixtures of these. Suitable emulsifying agents may be naturally-occurring phosphatides, for example soy bean lecithin, and esters or partial esters derived from fatty acids and hexitol anhydrides, for example sorbitan monooleate, and condensation products of the said partial esters with ethylene oxide, for example polyoxy-ethylene sorbitan monooleate. The emulsions may also contain sweetening, flavouring agents, preservatives and antioxidants.
Syrups and elixirs may be formulated with sweetening agents, for example glycerol, propylene glycol, sorbitol or sucrose. Such formulations may also contain a demulcent, a preservative, flavoring and coloring agents and antioxidant.
The pharmaceutical compositions may be in the form of a sterile injectable aqueous solutions. Among the acceptable vehicles and solvents that may be employed are water, Ringer""s solution and isotonic sodium chloride solution.
The sterile injectable preparation may also be a sterile injectable oil-in-water microemulsion where the active ingredient is dissolved in the oily phase. For example, the active ingredient may be first dissolved in a mixture of soybean oil and lecithin. The oil solution then introduced into a water and glycerol mixture and processed to form a microemulation.
The injectable solutions or microemulsions may be introduced into a patient""s blood-stream by local bolus injection. Alternatively, it may be advantageous to administer the solution or microemulsion in such a way as to maintain a constant circulating concentration of the instant compound. In order to maintain such a constant concentration, a continuous intravenous delivery device may be utilized. An example of such a device is the Deltec CADD-PLUS(trademark) model 5400 intravenous pump.
The pharmaceutical compositions may be in the form of a sterile injectable aqueous or oleagenous suspension for intramuscular and subcutaneous administration. This suspension may be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents which have been mentioned above. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, for example as a solution in 1,3-butane diol. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose any bland fixed oil may be employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid find use in the preparation of injectables.
Compounds of Formula A may also be administered in the form of a suppositories for rectal administration of the drug. These compositions can be prepared by mixing the drug with a suitable non-irritating excipient which is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug. Such materials include cocoa butter, glycerinated gelatin, hydrogenated vegetable oils, mixtures of polyethylene glycols of various molecular weights and fatty acid esters of polyethylene glycol.
For topical use, creams, ointments, jellies, solutions or suspensions, etc., containing the compound of Formula A are employed. (For purposes of this application, topical application shall include mouth washes and gargles.)
The compounds for the present invention can be administered in intranasal form via topical use of suitable intranasal vehicles and delivery devices, or via transdermal routes, using those forms of transdermal skin patches well known to those of ordinary skill in the art. To be administered in the form of a transdermal delivery system, the dosage administration will, of course, be continuous rather than intermittent throughout the dosage regimen.
As used herein, the term xe2x80x9ccompositionxe2x80x9d is intended to encompass a product comprising the specified ingredients in the specific amounts, as well as any product which results, directly or indirectly, from combination of the specific ingredients in the specified amounts.
When a compound according to this invention is administered into a human subject, the daily dosage will normally be determined by the prescribing physician with the dosage generally varying according to the age, weight, sex and response of the individual patient, as well as the severity of the patient""s symptoms.
In one exemplary application, a suitable amount of compound is administered to a mammal undergoing treatment for cancer. Administration occurs in an amount between about 0.1 mg/kg of body weight to about 60 mg/kg of body weight per day, preferably of between 0.5 mg/kg of body weight to about 40 mg/kg of body weight per day.
The compounds of the instant invention may also be co-administered with other well known therapeutic agents that are selected for their particular usefulness against the condition that is being treated. For example, the compounds of the instant invention may also be co-administered with other well known cancer therapeutic agents that are selected for their particular usefulness against the condition that is being treated. Included in such combinations of therapeutic agents are combinations of the instant farnesyl-protein transferase inhibitors and an antineoplastic agent. It is also understood that such a combination of antineoplastic agent and inhibitor of farnesyl-protein transferase may be used in conjunction with other methods of treating cancer and/or tumors, including radiation therapy and surgery.
Examples of an antineoplastic agent include, in general, microtubule-stabilizing agents (such as paclitaxel (also known as Taxol(copyright)), docetaxel (also known as Taxotere(copyright)), epothilone A, epothilone B, desoxyepothilone A, desoxyepothilone B or their derivatives); microtubule-disruptor agents; alkylating agents, anti-metabolites; epidophyllotoxin; an antineoplastic enzyme; a topoisomerase inhibitor; procarbazine; mitoxantrone; platinum coordination complexes; biological response modifiers and growth inhibitors; hormonal/anti-hormonal therapeutic agents and haematopoietic growth factors.
Example classes of antineoplastic agents include, for example, the anthracycline family of drugs, the vinca drugs, the mitomycins, the bleomycins, the cytotoxic nucleosides, the taxanes, the epothilones, discodermolide, the pteridine family of drugs, diynenes and the podophyllotoxins. Particularly useful members of those classes include, for example, doxorubicin, carminomycin, daunorubicin, aminopterin, methotrexate, methopterin, dichloro-methotrexate, mitomycin C, porfiromycin, 5-fluorouracil, 6-mercaptopurine, gemcitabine, cytosine arabinoside, podophyllotoxin or podo-phyllotoxin derivatives such as etoposide, etoposide phosphate or teniposide, melphalan, vinblastine, vincristine, leurosidine, vindesine, leurosine, paclitaxel and the like. Other useful antineoplastic agents include estramustine, cisplatin, carboplatin, cyclophosphamide, bleomycin, tamoxifen, ifosamide, melphalan, hexamethyl melamine, thiotepa, cytarabin, idatrexate, trimetrexate, dacarbazine, L-asparaginase, camptothecin, CPT-11, topotecan, ara-C, bicalutamide, flutamide, leuprolide, pyridobenzoindole derivatives, interferons and interleukins.
The preferred class of antineoplastic agents is the taxanes and the preferred antineoplastic agent is paclitaxel.
Radiation therapy, including x-rays or gamma rays which are delivered from either an externally applied beam or by implantation of tiny radioactive sources, may also be used in combination with the instant inhibitor of farnesyl-protein transferase alone to treat cancer.
Additionally, compounds of the instant invention may also be useful as radiation sensitizers, as described in WO 97/38697, published on Oct. 23, 1997, and herein incorporated by reference.
The instant compounds may also be useful in combination with other inhibitors of parts of the signaling pathway that links cell surface growth factor receptors to nuclear signals initiating cellular proliferation. Thus, the instant compounds may be utilized in combination with a compound which has Raf antagonist activity. The instant compounds may also be co-administered with a compounds that is a selective inhibitor of geranylgeranyl protein transferase type I, a selective inhibitor of farnesyl-protein transferase and/or a compound that is a dual inhibitor of geranylgeranyl protein transferase type I and farnesyl-protein transferase. Such a selective inhibitor or dual inhibitor may be an inhibitor that is competitive with the binding of the CAAX-containing protein substrate of farnesyl-protein transferase or may be a prenyl pyrophosphate compeptitive inhibitor.
In particular, the compounds disclosed in the following patents and publications may be useful as farnesyl pyrophosphate-competitive inhibitor component of such a composition: U.S. Ser. Nos. 08/254,228 and 08/435,047. Those patents and publications are incorporated herein by reference.
In practicing methods of this invention, which comprise administering, simultaneously or sequentially or in any order, two or more of a protein substrate-competitive inhibitor and a prenyl pyrophosphate-competitive inhibitor, such administration can be orally or parenterally, including intravenous, intramuscular, intraperitoneal, subcutaneous, rectal and topical routes of administration. It is preferred that such administration be orally. It is more preferred that such administration be orally and simultaneously. When the protein substrate-competitive inhibitor and prenyl pyrophosphate-competitive inhibitor are administered sequentially, the administration of each can be by the same method or by different methods.
The instant compounds may also be useful in combination with an integrin antagonist for the treatment of cancer, as described in U.S. Ser. No. 09/055,487, filed Apr. 6, 1998, which is incorporated herein by reference.
As used herein the term an integrin antagonist refers to compounds which selectively antagonize, inhibit or counteract binding of a physiological ligand to an integrin(s) that is involved in the regulation of angiogenisis, or in the growth and invasiveness of tumor cells. In particular, the term refers to compounds which selectively antagonize, inhibit or counteract binding of a physiological ligand to the xcex1vxcex23 integrin, which selectively antagonize, inhibit or counteract binding of a physiological ligand to the xcex1vxcex25 integrin, which antagonize, inhibit or counteract binding of a physiological ligand to both the xcex1vxcex23 integrin and the xcex1vxcex25 integrin, or which antagonize, inhibit or counteract the activity of the particular integrin(s) expressed on capillary endothelial cells. The term also refers to antagonists of the xcex1vxcex26, xcex1vxcex28, xcex11xcex21, xcex12xcex21, xcex15xcex2, xcex16xcex21 and xcex16xcex24 integrins. The term also refers to antagonists of any combination of xcex1vxcex23, xcex1vxcex25, xcex1vxcex26, xcex1vxcex28, xcex11xcex21, xcex12xcex21, xcex15xcex21, xcex16xcex21 and xcex16xcex24 integrins. The instant compounds may also be useful with other agents that inhibit angiogenisis and thereby inhibit the growth and invasiveness of tumor cells, including, but not limited to angiostatin and endostatin.
Similarly, the instant compounds may be useful in combination with agents that are effective in the treatment and prevention of NF-1, restenosis, polycystic kidney disease, infections of hepatitis delta and related viruses and fungal infections.
If formulated as a fixed dose, such combination products employ the combinations of this invention within the dosage range described below and the other pharmaceutically active agent(s) within its approved dosage range. Combinations of the instant invention may alternatively be used sequentially with known pharmaceutically acceptable agent(s) when a multiple combination formulation is inappropriate.